Throughout this application various publications are referred to in parenthesis or brackets. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Breast cancer remains the major cause of cancer death in women in the developed world. Novel therapeutic modalities are needed for patients with tumors resistant to conventional therapies such as chemotherapy, hormonal treatment and external radiation. Recently Tazebay et al. [31, 41] found that more than 80% of human mammary cancers, but not normal healthy non-lactating breast tissue, express a sodium/iodide symporter (NIS) which was named the mammary gland NIS (mgNIS). Kilbane et al. [11] found NIS expression to be a feature of both fibroadenomata and breast carcinoma tissues.
NIS mediates iodide accumulation in the thyroid gland [2], and the capability to concentrate and organify iodide allows the use of radioactive iodine isotope 131I for the treatment of differentiated thyroid cancers and hyperthyroidism [10, 24]. However, as pointed out by Daniels and Harber [5], organification of iodide is unlikely to occur in breast cancer cells as the thyroid is the only organ known to organify iodide, a process that involves the conversion of inorganic iodide to an organic form by conjugation to tyrosine residues on the protein thyroglobulin, a precursor to iodinated forms of thyroid hormone [30]. The organification process causes radioiodine to be retained within the thyroid gland for several days [16]. This relatively long retention time matches the physical half-life of 131I (8 days) and allows a significant radiation dose to be delivered to the tumor.
NIS gene expression has been detected in several tissues in humans, including the thyroid gland, mammary gland, salivary glands, and gastric mucosa [43].
Several studies have reported transfection of NIS into different non-thyroid or undifferentiated thyroid tumors for the purpose of subsequent therapy with 131I [1, 3, 15, 17, 21, 27]. In all of these studies, although 131I uptake in NIS-expressing tumors was substantial (up to 27% injected dose in [27]), the residence times of 131I in the tumors were relatively short and no tumor shrinkage was observed [1, 3, 27]. In a recent report by Spitzweg et al. [28], impressive therapeutic results were seen in NIS-transfected prostate tumor xenografts in mice when treated with a very high single 3 mCi dose of 131I. However, as no biodistribution and no dose-escalation studies were reported, it is unclear why such high dose was administered. The lack of therapeutic gains observed by other investigators [1, 3, 27] can be attributable to the long physical half-life (8 days) and decay properties of 131I, as the beta-particles emitted by 131I are low energy (Eaverage=0.134 MeV) and have an optimal tissue range of only 2.6-5.0 mm [22].
Several different approaches to circumvent the problem of insufficient iodide radiation dose to NIS-expressing tumors have been suggested. Daniels and Haber [5] and Nakamoto [21] suggested that pharmacologic modulation of fast cellular radioiodide efflux from breast cancer cells might be possible by administering lithium salts which increase radioiodide half-life in thyroid tumors. Boland et al. [1] proposed to improve the efficiency of NIS gene transfer and thus the iodide uptake capacity of the target tissue by the use of modified vectors and/or higher viral doses. The same authors also proposed to increase the biological half-life of radioiodide in the tumor tissues by coupling transfer of the NIS gene with the delivery of a gene involved in the iodide organification process, such as thyroperoxidase. Such an approach is not easy to implement because of the inherent complexity of gene therapy procedures especially in the case of 2-gene transfer and the difficulty in transfecting only the target tissue (tumor) in vivo.
A short-lived isotope of technetium 99mTc is used in ˜90% of all diagnostic nuclear medicine procedures [e.g., 42]. It has long been recognized by nuclear medicine practitioners that due to their common ionic characteristics, iodide and 99mTc-pertechnetate (99mTcO4−) behave similarly following intravenous administration [23]. Like iodide, 99mTcO4− localizes in the thyroid, salivary glands, gastric mucosa, and choroid plexus of the brain. It is trapped but not organified in the thyroid gland and is used in nuclear medicine as an alternative to Na123I for assessing thyroid condition.
Rhenium is a chemical analogue of technetium and exhibits practically identical chemical and biodistribution properties [6]. 188-Rhenium (188Re), a powerful beta-emitting radionuclide (Eaverage=0.764 MeV) with a 16.7 hour half-life has been recently used in a number of therapeutic applications in humans including cancer radioimmunotherapy, palliation of skeletal bone pain, and endovascular brachytherapy to prevent restenosis after angioplasty [8, 12, 25], as well as in the pre-clinical development of novel therapeutics [4, 19]. 186-Rhenium (186Re), which has a half-life of 3.7 days and Eaverage=0.362 MeV, is also being used in clinical applications [33-36]. Because of its chemical similarity to pertechnetate, the perrhenate anion (188ReO4−) is concentrated in thyroid and stomach [14]. Co-injected 99mTcO4−, 125I−, and 188ReO4− have similar uptake and biodistribution in NIS-expressing (thyroid, stomach, salivary gland) and non-expressing tissues in normal, healthy mice, with the exception of the thyroid gland where only 125I− is retained by organification [32]. In contrast, a study employing rat thyroid NIS expressed in Xenopus laevis oocytes found that ReO4− is a potent blocking agent for NIS, second to only perchlorate (ClO4−), and that ReO4− is transported via NIS only to a very small extent and only when the concentration of ReO4− is high [44]. Accordingly, the ability of NIS to mediate the transport of ReO4− in general, and its potential for doing so in tumor cells in particular, have not been resolved.